Safety, efficacy, and <scp>PK</scp>/<scp>PD</scp> of vorasidenib in previously treated patients with <scp>m</scp><i>IDH1/2</i> hematologic malignancies: A phase 1 study
Authors: Courtney D. DiNardo, Stéphane De Botton, Daniel A. Pollyea, Richard M. Stone, Jessica K. Altman, Amir T. Fathi, Tharin Limsakun, Min Liang, Sung Choe, Mohammad Hossain, Adriana E. Tron, Qian Meng, Stephanie M. Kapsalis, Shuchi S. Pandya, Eytan M. Stein
Journal: American Journal of Hematology (2023)

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in ~23% of patients with acute myeloid leukemia (AML) and ~7% with myelodysplastic syndrome (MDS).1, 2 These mutations lead to the accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG), which competitively inhibits α-ketoglutarate-dependent enzymes, causing epigenetic dysregulation and impaired hematopoietic differentiation, ultimately promoting oncogenesis.2, 3 Selective mutant IDH (mIDH) 1 and 2 inhibitors (ivosidenib, olutasidenib and enasidenib) are approved for patients with hematologic cancers, but isoform switching between mIDH1 and mIDH2 has emerged as a mechanism of resistance.4 Vorasidenib (AG-881) is an investigational, dual mIDH1/2 inhibitor that may prevent isoform switching.5 We conducted an open-label, first-in-human, phase 1, dose-escalation study of vorasidenib in patients with mIDH1/2 advanced hematologic malignancies (NCT02492737). Eligibility criteria included: aged ≥18 years, having AML and failed prior treatment with an approved IDH inhibitor, or having other relapsed/refractory advanced hematologic malignancies and having failed previous standard therapy, and having a documented IDH1 and/or IDH2 mutation. Ineligibility criteria were: hematopoietic stem cell transplant within 60 days or systemic anticancer therapy or investigational agent within 14 days of vorasidenib first dose. All patients provided written informed consent. The study adhered to the Declaration of Helsinki and the International Council for Harmonisation Guidelines for Good Clinical Practice. The protocol was approved by each study site's institutional review board/ethics committee. All patients received vorasidenib on day −3, followed by safety and pharmacokinetic/pharmacodynamic (PK/PD) assessments over 72 h. Vorasidenib was then administered orally, once daily (QD), in 28-day cycles. Seven vorasidenib dose levels were tested (from 25 to 1100 mg). Criteria for dose escalation and dose-limiting toxicities are detailed in the Supplementary Material. Maximum tolerated dose (MTD) was assessed in all patients who experienced a dose-limiting toxicity (DLT) during cycle 1 or who received ≥75% of vorasidenib doses during cycle 1 and had sufficient safety data to conclude that a DLT had not occurred. The full analysis set included patients who received ≥1 vorasidenib dose. Primary objectives were to determine the MTD, or recommended phase 2 dose, and to assess the safety and tolerability of vorasidenib in this population. Patients were enrolled from July 23, 2015, to March 21, 2018, at sites in the United States and France (Table S1). Baseline demographics and clinical characteristics are summarized in Table S2. Overall, 46 patients received vorasidenib: 34 with AML, 11 with MDS, and 1 with angioimmunoblastic T-cell lymphoma (AITL). In total, 31 (67.4%) patients had IDH2 mutations only (mean variant allele frequency [VAF] 34.92% [standard deviation (SD), 8.59%; range, 13.32–45.03%; n = 18]); 9 (19.6%) patients had IDH1 mutations only (mean VAF 37.49% [SD, 2.58; range, 34.59–41.13%; n = 5]); and 4 (8.7%) patients had co-occurring IDH1 and IDH2 mutations (of these, 2 had received prior enasidenib therapy, 1 had received prior ivosidenib therapy, and 1 patient with MDS had not received prior IDH-inhibitor therapy). Overall, 35/46 (76.1%; 34 with AML, 1 with MDS) patients received an IDH inhibitor before enrollment; 16/46 (34.8%) patients received an IDH inhibitor as their last prior regimen (all had AML). The median number of vorasidenib treatment cycles was 3 (range, 0–24); median duration of treatment was 2.2 (range, 0.0–22.6) months. Overall, 8/46 (17.4%) patients had exposures to vorasidenib lasting ≥6 months (Figure 1A), of whom 5 were prior IDH-inhibitor naive. Of the patients with AML, 21/34 (61.8%) discontinued vorasidenib due to progressive disease (PD), 10/34 (29.4%) due to adverse events (AEs), and 3/34 (8.8%) due to withdrawal of consent. The patient with AITL discontinued vorasidenib due to PD. Of patients with MDS, 4/11 (36.4%) discontinued due to PD, 2/11 (18.2%) due to AEs, 2/11 (18.2%) to proceed to stem cell transplant, 1/11 (9.1%) withdrew consent, and 2/11 (18.2%) were transferred to single-patient FDA Investigational New Drug Applications and continued to receive vorasidenib for >5 years. All patients experienced ≥1 AE, and 4/46 (8.7%) patients experienced serious AEs assessed as treatment-related (Table S3). The most common AEs were fatigue, increased ALT, increased blood alkaline phosphatase, and diarrhea (Table S4). Although no DLTs occurred, 1100 mg QD was deemed intolerable due to AEs of increased alanine aminotransferase (ALT) in 5/6 patients (83.3%, Table S4), with 4/6 (66.6%) experiencing grade 2 elevations. Vorasidenib 600 mg QD was the last tolerable dose evaluated. No on-treatment deaths (n = 9) or discontinuations due to AEs (n = 10) were considered treatment-related (Tables S5 and S6). The best overall response (BOR) for patients with AML was morphologic leukemia-free state (MLFS) in 2/34 (5.9%) patients; 22/34 (64.7%) patients experienced stable disease; 6/34 (17.6%) patients had PD; response was not evaluable in 4/34 (11.8%) patients (Figure 1A). In patients with MDS, BOR was complete remission (CR) in 3/11 patients (27.3%) and marrow CR in 1/11 (9.1%) patients; 5/11 (45.5%) patients experienced stable disease; treatment failure and PD were experienced by 1/11 (9.1%) patients each. Objective response rates were 5.9% (95% confidence interval [CI], 0.7–19.7) for patients with AML, 36.4% (95% CI, 10.9–69.2) for patients with MDS, and 27.3% for prior IDH inhibitor−naive patients. Overall, 6/31 (19.4%) patients who were transfusion−dependent at baseline became transfusion independent, per the definition of ≥28 days between consecutive transfusions. PK/PD were evaluated in all patients who received ≥1 vorasidenib dose and had ≥1 evaluable blood sample (Table S7). At cycle 1 day 15, vorasidenib had a median Tmax of 0.97–2.0 h across dose levels, and geometric means for Cmax and AUC0–24 were correlated with increasing vorasidenib dose levels up to 600 mg QD; Cmax and AUC0–24 were lower for the 1100 mg QD dose than 600 mg QD (Table S7, Figure S1A). Across the study, plasma 2-HG levels generally decreased with increasing plasma vorasidenib concentrations (Table S7, Figure 1B, Figure S1B). In patients who received vorasidenib 400 mg QD, mean reductions in plasma 2-HG BRmin of −87.0% and −89.3% were observed at cycle 1 day 15 and cycle 2 day 1, respectively. Decreased plasma 2-HG levels were more pronounced in patients with MDS without prior IDH-inhibitor treatment than in those who had previously received IDH inhibitors, regardless of vorasidenib dose received (Figure 1C), though the numbers in this analysis were small. Of the patients with IDH1 and IDH2 comutations, 3/4 experienced a BOR of stable disease; plasma 2-HG levels reduced from 195, 1320, and 1960 ng/mL at screening to on-treatment minimums of 75.3, 65.3, and 109 ng/mL, respectively. Figure S2 shows baseline comutation data for patients grouped by BOR. Figure S3 illustrates VAF–PK/PD relationships in patients with MDS or AITL and AML, and lists their BOR. There was no change in IDH mutation burden (VAF) in most patients who received vorasidenib. Of the 3 patients who achieved a CR, all displayed a decrease in 2-HG, 1 displayed a decrease in VAF and no VAF data were available for the other 2, 2 did not report myeloblasts at baseline, and 1 reported 14% myeloblasts at baseline. Although no DLTs were reported with vorasidenib 1100 mg QD, the clinical study team determined this dose was not tolerable. Plasma pharmacokinetic parameters for vorasidenib are generally negatively correlated with plasma 2-HG pharmacodynamic parameters, with decreases in plasma 2-HG greatest in patients who received vorasidenib 400 mg QD. This may have been a result of CYP3A4 auto-induction occurring at the higher dose levels and/or the interrupted vorasidenib dosing in the 1100 mg QD cohort owing to ALT AEs. Based on the former, it is plausible that further plasma 2-HG decreases would not be achieved with doses >600 mg QD. A dose-exposure/2-HG relationship could not be established in patients who received >600 mg QD, suggesting doses from 400 to 600 mg QD could be feasible. For most patients with AML, the BOR on vorasidenib treatment was stable disease, while 3 patients with MDS achieved CR. The difference in objective response rate for patients with AML and MDS is likely related to the enrollment criteria, which required patients with AML to have failed prior IDH-inhibitor therapy. Thus, all patients with AML had received prior enasidenib or ivosidenib, versus only 1/11 patients with MDS. It is likely that the patients with AML in this study were more resistant to IDH-inhibitor monotherapy, resulting in less favorable outcomes with vorasidenib treatment. Given its ability to inhibit both mIDH1 and mIDH2, vorasidenib is predicted to prevent isoform switching from evolving as a resistance mechanism if administered as initial IDH-inhibitor therapy. For instance, in 1 patient with a dual IDH mutation at baseline who previously achieved CRi on enasidenib treatment and then relapsed with a new IDH1 second-site mutation, a reduction in IDH1 VAF with vorasidenib was observed. In conclusion, in this patient population, vorasidenib treatment was tolerable up to doses of 600 mg QD. 2-HG suppression and evidence of clinical activity were observed in previously mIDH inhibitor−naive patients, but the suboptimal dose-efficacy profile in AML patients previously treated with mIDH inhibitors limited the evaluation of vorasidenib's dual mutant-enzyme inhibitor properties to prevent isoform switching in this population; therefore, development of vorasidenib in AML was not pursued. Based on vorasidenib's brain-penetrant activity,5 its development is currently focused on patients with mIDH glioma.6 C.D.D., S.d.B., D.A.P., R.M.S., J.K.A., A.T.F., and E.M.S. participated in the recruitment and treatment of patients in the trial and the collection of data. T.L., M.L., S.C., M.H., A.E.T., Q.M., S.M.K., and S.S.P. performed the data analysis. S.C., M.H., A.E.T., Q.M., and S.M.K. oversaw drafting of the manuscript. All authors participated in clinical data interpretation and manuscript development, and approved the submitted version. Medical writing assistance was provided by David Pertab, PhD, and Christine Ingleby, DPhil, CMPP, Excel Medical Affairs, Glasgow, UK, and supported by Servier Pharmaceuticals LLC. The study was supported by Agios Pharmaceuticals, Inc. Servier Pharmaceuticals LLC, which funded medical writing assistance, has completed acquisition of Agios' oncology business. C.D.D. has consulted for AbbVie and Servier; received research funding from AbbVie, Astex, BMS, Cleave, Foghorn, Forma, Immune-Onc, Loxo, and Servier; received honoraria from Astellas, Bluebird Bio, BMS, Foghorn, Gilead, Immune-Onc, Jazz, Novartis, Kura, Servier, and Takeda; has a membership of the board of directors or advisory roles with Genmab, GSK, Kura, and Notable Labs; and has stock options with Notable Labs. S.D.B. has received honoraria from AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has acted as a consultant or advisor to Bristol Myers Squibb, GlaxoSmithKline, Servier, and Syndax; has participated in speakers' bureau for AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has received research funding to his institution from Auron Therapeutics and Forma Therapeutics; and has received travel, accommodations, or expenses from AbbVie and Servier. D.A.P. has acted as a consultant or advisor to AbbVie, Celgene, Bristol Myers Squibb, Takeda, Foghorn, Aprea, Genentech, Syros, Novartis, Gilead, Astellas, Karyopharm, Syndax, Jazz, Bergen Bio, Arcellx, AstraZeneca, Kura, Ryvu, Magenta, Qihan, Zentalis, Medivir, HiberCell, and has received research funding from AbbVie, Bristol Myers Squibb, Teva, and Karyopharm. R.M.S. reports grants and personal fees from AbbVie, Agios, and Novartis; personal fees from Actinium, Astellas, BioLineRx, Celgene, Daiichi-Sankyo, Elevate, GEMoaB, Janssen, Jazz, MacroGenics, Onconova, Syndax, Syntrix, Syros, Takeda, Trovagene, BerGenBio, Foghorn Therapeutics, GlaxoSmithKline, Aprea, Innate, Amgen, BMS, Boston Pharmaceuticals, Aptevo, Epizyme, Kura Oncology, and grants from AROG, outside the submitted work. J.K.A. has acted as a consultant or advisor for AbbVie, Astellas Pharma, BioSight, Bluebird Bio, Curio, Gilead, Kura Oncology, Kymera, Stemline Therapeutics, and Syros; received research funding from Servier; and received travel, accommodations, or travel-related expenses from BioSight. A.T.F. has consulted for AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Celgene, EnClear, Forma, Genentech, Immunogen, Ipsen, Kite, Mablytics, Novartis, Orum, PureTech, Servier, and Takeda; and has received funding for clinical trials from AbbVie, Agios/Servier, and Celgene/Bristol Myers Squibb. E.M.S. has acted as a consultant or advisor to Novartis, Janssen, BMS/Celgene, Agios, Jazz Pharmaceuticals, Menarini, Genentech, Genesis Pharma, AbbVie, Neoleukin Therapeutics, Gilead Sciences, Syndax, OnCusp Therapeutics, Immunogen, CTI BioPharma Corp, Foghorn Therapeutics, Servier, Calithera Biosciences, Daiichi Sankyo, Aptose Biosciences, Ono Pharmaceutical, Blueprint Medicines, GEMoaB, Jnana Therapeutics, and Debiopharm Group; has stock or ownership in Auron Therapeutics; and has received research funding to his institution from Eisai, BMS/Celgene, Bayer, Agios, BioTheryX, Syros Pharmaceuticals, Servier, Foghorn Therapeutics, Syndax, Gilead Sciences, Cleave Biosciences, Prelude Therapeutics, and Loxo/Lilly. T.L., S.C., M.H., A.E.T., Q.M., S.M.K., and S.S.P. are employees of Servier. M.L., S.C., M.H., A.E.T., S.M.K., and S.S.P. were employees of Agios at the time of conducting these studies. All patients provided written informed consent before participation. Study-level clinical data from this study (including the protocol) will be made available upon reasonable request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include deidentified individual participant data. The data for this request will be available after a data access agreement has been signed. Please send your data sharing request to https://clinicaltrials.servier.com/data-request-portal/. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.